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Impact of rifampicin-inhibitable transport on the liver distribution and tissue kinetics of erlotinib assessed with PET imaging in rats

BACKGROUND: Erlotinib is an epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitor approved for treatment of non-small cell lung cancer. The wide inter-individual pharmacokinetic (PK) variability of erlotinib may impact treatment outcome and/or toxicity. Recent in vivo studies r...

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Detalles Bibliográficos
Autores principales: Amor, Dorra, Goutal, Sébastien, Marie, Solène, Caillé, Fabien, Bauer, Martin, Langer, Oliver, Auvity, Sylvain, Tournier, Nicolas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095934/
https://www.ncbi.nlm.nih.gov/pubmed/30116910
http://dx.doi.org/10.1186/s13550-018-0434-0
Descripción
Sumario:BACKGROUND: Erlotinib is an epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitor approved for treatment of non-small cell lung cancer. The wide inter-individual pharmacokinetic (PK) variability of erlotinib may impact treatment outcome and/or toxicity. Recent in vivo studies reported a nonlinear uptake transport of erlotinib into the liver, suggesting carrier-mediated system(s) to mediate its hepatobiliary clearance. Erlotinib has been identified in vitro as a substrate of organic anion-transporting polypeptide (OATP) transporters which expression does not restrict to hepatocytes and may impact the tissue uptake of erlotinib in vivo. RESULTS: The impact of rifampicin (40 mg/kg), a potent OATP inhibitor, on the liver uptake and exposure to tissues of (11)C-erlotinib was investigated in rats (4 animals per group) using positron emission tomography (PET) imaging. Tissue pharmacokinetics (PK) and corresponding exposure (area under the curve, AUC) were assessed in the liver, kidney cortex, abdominal aorta (blood pool) and the lungs. The plasma PK of parent (11)C-erlotinib was also measured using arterial blood sampling to estimate the transfer rate constant (k(uptake)) of (11)C-erlotinib from plasma into different tissues. PET images unveiled the predominant distribution of (11)C-erlotinib-associated radioactivity to the liver, which gradually moved to the intestine, thus highlighting hepatobiliary clearance. (11)C-erlotinib also accumulated in the kidney cortex. Rifampicin did not impact AUC(aorta) but reduced k(uptake, liver) (p < 0.001), causing a significant 27.3% decrease in liver exposure (p < 0.001). Moreover, a significant decrease in k(uptake, kidney) with a concomitant decrease in AUC(kidney) (− 30.4%, p < 0.001) were observed. Rifampicin neither affected k(uptake, lung) nor AUC(lung). CONCLUSIONS: Our results suggest that (11)C-erlotinib is an in vivo substrate of rOATP transporters expressed in the liver and possibly of rifampicin-inhibitable transporter(s) in the kidneys. Decreased (11)C-erlotinib uptake by elimination organs did not translate into changes in systemic exposure and exposure to the lungs, which are a target tissue for erlotinib therapy.